Cytochrome P450 (CYP) enzymes metabolize endogenous and xenobiotic compounds. CYP3A4 belongs to the CYP3A subfamily and is the most abundant CYP enzyme. CYP3A4 is involved in metabolizing 45-60% of all currently used drugs (1), including several statins—cholesterol-lowering HMG-CoA reductase inhibitors. However, CYP3A4 activity shows wide inter-individual variation, influencing drug response and toxicity. While genetic factors are thought to be main contributors to inter-individual differences in CYP3A4 activity (2), currently known CYP3A4 polymorphisms cannot account for the observed variability.
Genetic variants in CYP3A4 that change the amino acid sequence are rare (<1%). A more common variant, CYP3A4*1B, in the 5′-flanking region, has been associated with drug response and diseases (3,4), but results are inconsistent (5-7), and its function remains controversial (3,8-10). Moreover, CYP3A4*1B is in linkage disequilibrium (LD) with the adjacent CYP3A5 (11), encoding a similar but usually less abundant CYP enzyme that could have accounted for any linked clinical phenotype (12).
Further suspected CYP3A4 polymorphisms include a TGT insertion (13), an enhancer region SNP (rs2737418) (14), and an intron7 SNP (rs4646437) (15). While reporter gene assays suggested an effect for the TGT insertion and for rs2737418, the in vivo significance of TGT remains unresolved (13), while results on CYP3A4 mRNA and enzyme activity were contradictory for rs2737418 (14). The intron7 SNP rs4646437 was found to be associated with CYP3A4 protein/enzyme activity, but only in livers from males (15). Therefore, the role of functional polymorphisms in CYP3A4 remains uncertain.
Single nucleotide polymorphisms (SNPs) are useful as biomarkers for predicting disease susceptibility or progression, or as a guide for individualized therapy, including drug therapy.
What are lacking are tools for predicting the likelihood that a particular patient will be responsive to a particular therapeutic agent, and in particular, identifying polymorphisms to which a CYP3A4 agent will be sensitive or resistant. Also lacking are tools for profiling genetic factors influencing sensitivity and resistance of patients to such therapeutic agents. Such tools, and the resulting gene expression profiles, would be predictive of treatment response of a patient to a particular drug, and would allow for increased predictability regarding efficacy, adverse drug reactions, chemosensitivity or chemoresistance of such patients to enable the design of optimal treatment regimens for patients, or to enable drug development in early clinical trials avoiding unexpected toxicities in poor metabolizers.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objects and advantages of the invention may be realized and attained as particularly pointed out in the appended claims.